Infectious agents commonly enter the host across a mucosal tissue such as the oral mucosa and other mucosa of the alimentary canal, the respiratory tract including olfactory and conjunctival mucosa, the mammary glands, and the genitourinary tract. The mucosal immune system provides a secretory immunoglobulin response to prevent infectious agents at these points of entry.
The secretory immune response includes clonal proliferation of antigen-specific B cells and progressive isotype switching by the B cell progeny to all subclasses of IgG- and IgA-secreting cells. Antigens such as microorganisms, proteins, polysaccharides, etc., that are encountered at a mucosal site can elicit local production of antibodies into the secretions that bathe the mucosal surface at the site, as well as other mucosal sites.
Secretory and circulating IgA production often exceeds that of other immunoglobulin isotypes. Secretory IgA as well as IgM and all subclasses of IgG have been found in virtually all external secretions, including tears, saliva, colostrum and milk, and in the mucous secretions of the respiratory, intestinal and genitourinary tracts.
The secretory IgA performs a protective role in the prevention of infectious diseases and for the inhibition of allergic reactions at mucosal surfaces. Secreted IgA neutralizes biologically active antigens, prevents uptake of antigens from the intestinal tract, and inhibits adherence of bacteria to epithelial surfaces.
Once antigen penetrates the mucosal epithelial cells, antigen-presenting cell-dependent activation of paracortical T cells and germinal center B cells within the Peyer's Patches is observed. However, the inductive stimuli required for differentiation of IgA-committed B cells is deferred until B cells have migrated through efferent lymphatics into the mesenteric lymph nodes after departure from the Peyer's Patches. Ultimately, IgA-committed, antigen-sensitized B cells enter the circulation through the lymph to populate various exocrine glands and mucosal epithelia throughout the body. Under local influences which include information provided by helper T cells, by the antigen and other biochemical mediators, terminal differentiation into IgA-secreting plasma cells occurs.
Tissue-selective trafficking of memory and effector T and B lymphocytes is mediated by a unique combination of adhesion molecules and chemokines Chemokines contribute to both lymphocytes exit from circulation and localization and retention within tissues. Memory T lymphocytes selectively re-circulate back through tissues including skin and intestines and other mucosal tissues. Chemokines and their receptors help control the movement of memory lymphocytes subsets through skin and gut. Effector T cells homing to the intestine and GALT express high levels of a4b7, whose ligand, MAdCAM-1 is expressed in the intestinal lamina propria and Peyers Patches. These mucosal T cells also express CCR9, whose ligand, TECK (CCL25) is selectively expressed by small intestinal epithelial cells. DC's which home to the mucosae express CCR10 which is the receptor for the chemokines Mec or c-TACK. (Campbell et al., J. Exp. Med. 2002, 195:(1) 135-141. Johansson-Lindbom et al., J. Exp. Med. 2003. 198(6), 963-969, which is incorporated herein by reference.)
Cutaneous lymphocyte-associated antigen (CLA+) memory T cells are preferentially targeted by CTACK and MEC. (Morales et al., 1999 PNAS, 96(25) 14470-14475, Jarmin et al., 2000 J. Immunol. 164:3460-3464). Therefore, CTACK, MEC and their receptors control movement of memory lymphocyte subsets in skin and gut.
Subset of circulating a4b7+ integrin lymphocytes from the small intestine co-express CCR9 and respond to TECK, and all T lymphocytes in the small intestinal epithelium express CCR9 (Zabel et al., 1999 J. Exp. Med. 190:1241-1256). Therefore, TECK and CCR9 play a critical role in lymphocyte biology in the mucosae.
Mucosal epithelia are major siteof secretory IgA by resident plasma cells. B cells secreting IgA also migrate preferentially to mucosae and express a4b7. B cells from spleen, MLN, and Peyer's patches express CCR9 (Butcher et al., 1999 Adv. Immunol. 72: 209-253, Kunkel et al., 2000 J. Exp. Med. 192:761-768). Therefore, TECK and CCR9 participate in localization of B cells that secrete IgA to mucosal sites.
Vaccine protocols can be improved by the delivery of agents that modulate a person's immune responses to induce an improved immune response. In some vaccination protocols in which the individual is administered a vaccine that exposes the individual to an immunogen against which the individual generates an immune response, an agent is provided that increases the immune response and/or selectively enhances a portion of the immune response (such as the cellular arm or the humoral arm) which is desirable to treat or prevent the particular condition, infection or disease.
Vaccines are useful to immunize individuals against target antigens such as allergens, pathogen antigens or antigens associated with cells involved in human diseases. Antigens associated with cells involved in human diseases include cancer-associated tumor antigens and antigens associated with cells involved in autoimmune diseases.
In designing such vaccines, it has been recognized that vaccines that produce the target antigen in cells of the vaccinated individual are effective in inducing the cellular arm of the immune system. Specifically, live attenuated vaccines, recombinant vaccines which use avirulent vectors, and DNA vaccines each lead to the production of antigens in the cell of the vaccinated individual which results in induction of the cellular arm of the immune system. On the other hand, killed or inactivated vaccines, and sub-unit vaccines which comprise only proteins do not induce good cellular immune responses although they do induce a humoral response.
A cellular immune response is often necessary to provide protection against pathogen infection and to provide effective immune-mediated therapy for treatment of pathogen infection, cancer or autoimmune diseases. Accordingly, vaccines that produce the target antigen in cells of the vaccinated individual such as live attenuated vaccines, recombinant vaccines that use avirulent vectors and DNA vaccines are often preferred.
While such vaccines are often effective to immunize individuals prophylactically or therapeutically against pathogen infection or human diseases, there is a need for improved vaccines. There is a need for compositions and methods that produce an enhanced immune response.
Likewise, while some immunotherapeutics are useful to modulate immune response in a patient there remains a need for improved immunotherapeutic compositions and methods.